This invention relates to antimicrobial and antineoplastic formulations or compositions useful for treating neurologic infections and cancers.
The cerebrospinal fluid (CSF) pathway system, which intimately bathes and permeates brain and spinal cord tissues, constitutes a circulatory system within the body. Although it has some similarities to systemic vascular and lymphatic circulation, its anatomical arrangement differs considerably. Indeed, this system has been named the xe2x80x9cthird circulationxe2x80x9d system. Due to the extensive area of CSF-tissue contact over the cerebral and spinal cord surfaces, in the paravascular Virchow-Robins spaces, and cerebral ventricles, the cerebrospinal fluid system constitutes a vast, complex and intimate avenue for access to central nervous tissue.
Disclosed herein are methods of treating critical infections and cancers of neuronal tissue using a perfusion of that tissue, methods of scrubbing out toxins and infectious particles, organisms or cells with appropriate fluids, methods of treating certain infections or treating certain cancers, and methods of delivering certain classes of agents. These methods are not disclosed in such documents as U.S. Pat. No. 4,758,431, which assert without discussion that one can incorporate an antibiotic or antineoplastic into an oxygenating emulsion. An intermittent perfusion like administration of the antineoplastic agent ACNU (3-[(4-amino-2-methyl-5-pyrimidinyl)-methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride, nimustine) that involves an Omaya reservoir and lumbar puncture was described by Ushio et al (J. Neuro-Oncology 38:207-212, 1998).
The invention provides, among other things, a method of treating in an animal an infection or cancer of a cerebrospinal tissue characterized by a risk of death, the method comprising: (a) injecting a physiologically acceptable fluid for cerebrospinal perfusion into a first catheter into the cerebrospinal pathway, which fluid for cerebrospinal agent, the agent selected for effectiveness against the disease as identified or diagnosed; (b) withdrawing fluid at a second catheter into the cerebrospinal pathway to create a flow and flow pathway between the first and second catheters; and (c) maintaining the flow for a period of time adapted to perfuse at least 1 CSF volume.
Also provided is a method of treating in an animal an infection or cancer of a cerebrospinal tissue comprising: (a) injecting a fluid for cerebrospinal perfusion into a first catheter into the cerebrospinal pathway, which fluid has an therapeutically effective amount an antimicrobial or antineoplastic agent, the agent selected for effectiveness against the disease as identified or diagnosed, wherein the fluid for cerebrospinal perfusion further comprises one or both of: (1) an emulsion-forming effective amount of a lipid composition comprised of lipids found in biological membranes, or (2) 0.05-2.0 g/dL albumin; (b) withdrawing fluid at a second catheter into the cerebrospinal pathway to create a flow and flow pathway between the first and second catheters; and (c) maintaining the flow for a period of time adapted to perfuse at least 1 CSF volume.
Further provided is a method of treating bacterial meningitis, bacterial encephalitis, brain abscesses, tuberculous meningitis, neurosyphilis, fungal meningitis or meningoencephalitis, parasitic CNS infections or viral CNS infections comprising: (a) injecting a physiologically acceptable fluid for cerebrospinal perfusion into a first catheter into the cerebrospinal pathway, which fluid for cerebrospinal perfusion has an infection-treating effective amount an antimicrobial agent, the antimicrobial agent selected for effectiveness against the infection as identified or diagnosed; (b) withdrawing fluid at a second catheter into the cerebrospinal pathway to create a flow and flow pathway between the first and second catheters; and (c) maintaining the flow for a period of time adapted to perfuse at least 1 CSF volume.
Additionally provided is a method of treating in an animal an infection of cerebrospinal tissue comprising: (a) injecting a fluid for cerebrospinal perfusion into a first catheter into the cerebrospinal pathway, which fluid has an infection-treating effective amount an antimicrobial agent, the antimicrobial agent selected for effectiveness against the infection as identified or diagnosed, wherein the antimicrobial agent is an antihelminthic, aminoglycoside antibacterial, amphenicol antibacterial, ansamycin antibacterial, xcex2-lactam antibacterial, lincosamide antibacterial, macrolide antibacterial, polypeptide antibacterial, tetracycline class antibacterial, cycloserine antibacterial, tuberin, quinolone class antibacterial, sulfonamide antibacterial, tuberculostatic antibacterial, antifungal, antiprotazoal or antiviral agent; (b) withdrawing fluid at a second catheter into the cerebrospinal pathway to create a flow and flow pathway between the first and second catheters; and (c) maintaining the flow for a period of time adapted to perfuse at least 1 CSF volume.
Further provided is a method of treating neurologic cancers such a gliomas, glioblastomas, astrocytomas, leptomeningeal carcinomas, leptomeningeal leukemia or lymphomas and metastatic cancers from outside the CNS by: (a) injecting a physiologically acceptable fluid for cerebrospinal perfusion into a first catheter into the cerebrospinal pathway, which fluid for cerebrospinal perfusion has an cancer-treating effective amount an antineoplastic agent or agents, the antineoplastic agent selected for effectiveness against the cancer as identified or diagnosed; (b) withdrawing fluid at a second catheter into the cerebrospinal pathway to create a flow and flow pathway between the first and second catheters; and (c) maintaining the flow for a period of time adapted to perfuse at least 1 CSF volume.
Additionally provided is a method of treating in an animal a cancer of the cerebrospinal tissue comprising: (a) injecting a fluid for cerebrospinal perfusion into a first catheter into the cerebrospinal pathway, which fluid has an cancer-treating effective amount an antineoplastic agent, the antineoplastic agent selected for effectiveness against the cancer as identified or diagnosed, wherein the antineoplastic agent is methotrexate (N-[4-[[(2-amino-4-hydroxy-6-pteridinyl)methyl]methylamino]benzoyl]glutamic acid), cytarabine (Ara-C; 4-amino-1-xcex2-D-arabinofuranosylcytosine), thiotepa (triethylenethiophosphoramide or 1,1xe2x80x2, 1xe2x80x3-phosphinothioylidynetrisaziridine), topotecan ((S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3xe2x80x2,4xe2x80x2:6,7]indolizino [1,2-b]-quinoline-3,14(4H, 12H)-dione), mafosfamide (an oxazaphosphorine from Baxter Oncology, Frankfurt, Del., which generates its active principle, 4-hydroxy-cyclophosphamide, without hepatic intervention), busulfan (1,4-bis(methanesulfonoxy)butane) or ACNU [(3-[(4-amino-2-methyl-5-pyrimidinyl)-methyl]-1-(2-chloroethyl)-1-nitrosourea hydrochloride]; (b) withdrawing fluid at a second catheter into the cerebrospinal pathway to create a flow and flow pathway between the first and second catheters; and (c) maintaining the flow for a period of time adapted to perfuse at least 1 CSF volume.
Still additionally provided is a method of treating a toxemia of cerebrospinal tissue, comprising: (a) injecting a physiologically acceptable fluid for cerebrospinal perfusion into a first catheter into the cerebrospinal pathway; (b) withdrawing fluid at a second catheter into the cerebrospinal pathway to create a flow and flow pathway between the first and second catheters; and (c) maintaining the flow for a period of time adapted to perfuse (i) at least 15 CSF volumes or (ii) sufficient volume to reduce a concentration of toxin causing the toxemia in the perfusate at least 5-fold.